Is LARGE1 p.Ser103= (c.309C>T) pathogenic?

LARGE1 p.Ser103= (c.309C>T) is classified Benign/Likely benign in LARGE1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-01). Common (popmax 6.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6.

How is Walker-Warburg syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

LARGE1 p.Ser103=

Q: What condition is associated with LARGE1 p.Ser103= (c.309C>T)?

LARGE1 p.Ser103= (c.309C>T) is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6, muscular dystrophy-dystroglycanopathy type B6 (ClinVar).

Q: How common is LARGE1 p.Ser103= (c.309C>T) in the general population?

LARGE1 p.Ser103= (c.309C>T) is common (popmax 6.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.309C>T · rs59349720 · VCV95174

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 6.4%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.85	GERP -1.9, phastCons 1
Overall
CADD	8.018	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.4% African / African-American · 4,800/75,048 alleles

Filtering AF 6.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.18%

Overall 0.331% 5,343/1,614,076 alleles · common exomes 2,623/1,461,738 · genomes 2,720/152,338 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.4%	16
Remaining individualsnot grpmax-eligible	0.371%	269
Admixed American	0.316%	316
Middle Eastern	0.231%	433
South Asian	0.0121%	8,281
European (non-Finnish)	0.00814%	12,292

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: LARGE1
Protein: p.Ser103=
Coding: c.309C>T
MANE Select: NM_133642
dbSNP: rs59349720
Type: single nucleotide variant
Location: chr22:33650466 (GRCh38)
Gene constraint: LOEUF 0.606 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.15 · 4 PDB
Residue 103: the 'disordered' region

Full LARGE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: muscular dystrophy-dystroglycanopathy type B6

For Walker-Warburg syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: <1 / 1 000 000 (United Kingdom)

Similar variants

LARGE1 p.Arg95Ter Pathogenic ★★ same condition
LARGE1 p.Glu509Lys Pathogenic/Likely pathogenic ★★ same condition
LARGE1 c.*155C>T Uncertain significance ★★ same condition
LARGE1 p.Ala149Ser Uncertain significance ★★ ⚠ same condition
LARGE1 p.Ala252Val Uncertain significance ★★ ⚠ same condition
LARGE1 p.Ala478Thr Uncertain significance ★★ ⚠ same condition
LARGE1 p.Ala635Thr Uncertain significance ★★ ⚠ same condition
LARGE1 p.Ala752Gly Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/large1-p-ser103 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown